Method for producing N-butyryl-4-amino-3-methyl-methyl benzoate and the novel compound N-(4-bromo-2-methylphenyl)butanamide

ABSTRACT

The present invention relates to an improved process for preparing methyl N-butyryl-4-amino-3-methylbenzoate and the novel chemical compound N-(4-bromo-2-methylphenyl)butanamide.

[0001] The present invention relates to an improved process forpreparing methyl N-butyryl4-amino-3-methylbenzoate and the novelchemical compound N-(4-bromo-2methylphenyl)butanarnide.

[0002]4′-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol)-2-yl]methyl]biphenyl-2carboxylicacid is a valuable angiotensin antagonist, in particular a valuableangiotensin II antagonist (see EP-A 502 314). In the following, thesecariboxylic acids are also known for short as antagonists.

[0003] In J. Med. Chem. 1993, 4040 a synthesis of the antagoist isdescribed which starts from methyl 4-amino-3-methylbenzoate (I) andreacts it with butyryl chloride to give methylN-butyryl-4-amino-3-methylbenzoate (II) (see the following reactionscheme (1)).

[0004] Compound (II) is then converted in further steps to theantagonist.

[0005] The required starting compound of the formula (I) is onlyaccessible in a disadvantageous manner. For instance, 4-nitro-m-xylene(III) can be used as the starting material and converted by oxidation to4-nitro-2-methylbenzoic acid (IV) (see Liebigs Ann. Chem. 144, 163(1867)), which is then esterified to methyl 4-nitro-2-methylbenzoate (V)(see Chem. Ber. 102, 2502 (1969)) and reduced to methyl4-amino-3-methylbenzoate (I) (see Chem. Ber. loc. cit.). This processfor preparing compound (II) is illustrated by the following reactionscheme (2).

[0006] As can be seen, the known process for preparing compound (II)consists of four individual steps, and the first step (III)→(IV) isparticularly disadvantageous because it requires long reaction times andleads only unselectively and therefore in low yields to (IV). Accordingto J.O.C. 32, 134 (1967), a reaction time of 20 hours is required andthe yields are from 22.5 to 27%.

[0007] There is accordingly still a need for a process for preparingcompound (II) which requires fewer steps and provides compound (II) inan advantageous manner.

[0008] A process has now been found for preparing methylN-butyryl-4-amino-3methylbenzoate (II), which is characterized in thato-toluidine (VI) is reacted with butyryl chloride to giveN-(2-methylphenyl)butanamide (VII), the latter is brominated to giveN-(4-bromo-2-methylphenyl)butanamide (VIII) and this is converted byreaction with carbon monoxide and methanol in the presence of apalladium catalyst to give methyl N-butyryl-4-amino-3-methylbenzoate(II). The following reaction scheme (3) illustrates the processaccording to the invention.

[0009] The stages (VII)→(VIII) and (VIII)→(II) are particularlysurprisingly advantageous because they deliver (VIII) and (II) each inyields of over 95%.

[0010] The first stage of the process according to the invention, thereaction of compound (VI) with butyryl chloride to give compound (VII)may be carried out, for example, by initially charging compound (VI) inan inert solvent, for example an aromatic solvent such as chlorobenzene,toluene or xylene, and then metering in butyryl chloride at temperaturesof, for example, 50 to 100° C. In addition to the desired compound(VII), this also results in o-toluidine hydrochloride, which can, ifdesired, be completely converted to the amide by further heating. Theprogress of the reaction can be followed via the formation of hydrogenchloride. To destroy any remaining butyryl chloride residues, methanolcan be added. After cooling the reaction solution, the amide (VII)precipitates and can be isolated, for example by filtration, in a purityof generally over 98% and in yields of genereally from 92 to 95%.

[0011] The second stage of the process according to the invention, thebromination of compound (VII) to compound (VIII) may be carried out, forexample, by initially charging the compound (VII) in acetic acid, addingfrom 1 to 1.3 molar quantity of elemental bromine together with furtheracetic acid at from 10 to 80° C., continuing to stir the mixture at from10 to 80° C. for from 20 minutes to 3 hours, then adding a waterquantity of from 0.5 to 5 times the volume, removing the precipitateformed, washing it with water and drying it under reduced pressure.Compound (VIII), i.e. N-(4-bromo-2-methylphenyl)butanamide can beobtained in this manner in yields of generally over 95% and in puritiesof generally over 99%.

[0012] The third step of the process according to the invention, theconversion of compound (VIII) by reaction with carbon monoxide andmethanol in the presence of a palladium catalyst to compound (II) may becarried out, for example, by initially charging the compound of theformula (VIII) and a palladium catalyst into a pressure vessel, thenadding a mixture of methanol, optionally one or more solvents other thanmethanol and a base, then pressurizing at from 90 to 160° C. to 2-30 barof carbon monoxide and maintaining this pressure until no more carbonmonoxide is taken up.

[0013] In the third step of the process according to the invention,methanol may serve as a reaction partner and solvent. Optionally, one ormore organic solvents other than methanol may additionally be used.Preferred additional organic solvents include hydrocarbons such ashexane, cyclohexane, heptane, benzene, toluene, the isomeric xylenes andmixtures thereof, chlorinated hydrocarbons such as chlorobenzene,dichlorobenzene, methylene chloride and hexachloroethane, nitriles suchas acetonitrile, amides such as dimethylformamide and ethers such asdioxane and tetrahydrofuran. The use of such solvents is advantageouswhere it increases the solubility of carbon monoxide in the solution.This reaction stage can then be carried out at relatively low pressures,which on the industrial scale in particular is associated with lowerapparatus and safety engineering demands.

[0014] The palladium catalysts used may, for example, be those of thePd(P Ph₃)₂X₂ type where Ph=optionally substituted phenyl and X=halogen,which may also be prepared in situ from PdX₂ and PPh₃. Thetriphenylphosphine component may also be added in excess. Based oncompound (VIII), for example, from 0.1 to 1 mol % of palladium catalystmay be used.

[0015] Examples of useful bases include carbonates, hydrogen carbonatesand acetates of alkali metals. However, preference is given to primary,secondary and tertiary amines, in particular tri-C₁-C₁₀-alkylamines.Based on 1 mol of compound (VIII), for example, from 0.9 to 5 mol,preferably from 1.05 to 2 mol, of base can be used.

[0016] The process according to the invention provides compound (II) inan only 3-step process in good yields and in good purities. The yield inthe process according to the invention over all three steps is generallyfrom 90 to 95%. This is a substantial improvement in accessibility tocompound (II) and to the antagonists preparable from compound (II).

[0017] One embodiment of the process according to the invention is asynthesis of (VIII) without intermediate isolation of compound (VII).This is technically advantageous, since the intermediate isolation of acompound always requires additional apparatus, which slow the processand generally reduce the yield by isolation losses and residues, forexample in mother liquors.

[0018] In this embodiment, the initial procedure is as described forpreparing compound (VII). The crude solution of (VII) obtained byamidation is freed of the inert solvent after butyrylation bydistillation. In order to remove remaining residues of the inertsolvent, water may be added to the melt of compound (VII) and distilledoff again. The crude (VII) obtained may then be admixed with a solventsuitable for bromination. This is preferably acetic acid, formic acid,propionic acid or mixtures thereof with water in any ratio and alsodilute mineral acids such as sulfuric acid or just water. Bromination inan inert solvent with addition of Lewis acids, for example aluminumchloride, aluminum bromide, iron bromide, or with addition of elementaliron, is likewise possible. Particular preference is given to aceticacid and also to mixtures of acetic acid and water. Bromine is addeddirectly to this reaction mixture at temperatures of from 10 to 130° C.,preferably from 30 to 60° C. Based on 1 mol of compound (VII), from 0.9to 1.1 mol of bromine to from 1 to 1.05 mol can be added.

[0019] Owing to the resulting hydrobromic acid, only half of thevaluable bromine used can be converted. Accordingly, this embodimentcontemplates using only from 0.45 to 0.95 mol of bromine for 1 mol ofcompound (VII) and carrying out the further bromination via reoxidationof hydrobromic acid using an oxidant, preferably hydrogen peroxide, in aquantity supplementary to 1 mol.

[0020] The bromination can also be carried out using hydrobromic acid,and adding an oxidant after its addition. For example, from 0.9 to 1.1mol of hydrobromic acid per mole of compound (VII) and an equivalentquantity of oxidant, preferably hydrogen peroxide, can be used. Ifappropriate, hydrobromic acid can also be used as a solution in water.Instead of hydrobromic acid, bromides can also be used, preferablypotassium bromide. Bromides can also be used as such or, for example, inaqueous solution.

[0021] A technical problem in all of the above-described syntheses isthat the product (VIII) of the bromination, owing to its solubilityproperties, precipitates after the reaction has proceeded to from about30 to 70% spontaneously and as a fine solid. The resulting suspensioncan only be stirred with difficulty. An industrial reaction canaccordingly only be carried out at huge cost and inconvenience.

[0022] This problem is surprisingly solved by carrying out thebromination in the form of simultaneous metering in (with a tolerance ofup to 20%, preferably from 10 to 20%, in the respective volume flowrates) of the bromine or the bromine and the oxidant on the one hand andthe crude (VII), optionally a mixture of (VII) and the solvent suitablefor bromination, on the other hand. The reactants may be metered into areservoir in which a portion of the solvent suitable for bromination ispresent. This embodiment is likewise part of the subject matter of theprocess according to the invention. Preferred initial charges includemixtures of acetic acid and water in a ratio of from 0.2:0.8 to 0.8:0.2.Particularly preferred 0.25:0.75 to 0.5:0.5. The crystallizationbehavior was also improved by adding and also compound (VIII) (slightlysoluble) to the reservoir before bromination to give-a suspension.

[0023] The compound of the formula (VII) is novel. The present inventionalso accordingly relates to the compound of the formula (VIII), i.e.N-(4-bromo-2methylphenyl)butanamide. This compound can be prepared asdescribed above. It provides the key substance in the process accordingto the invention for preparing the compound of the formula (II). Itsdiscovery facilitated improved access to the compound of the formula(II) and the antagonists preparable from it.

EXAMPLES Example 1

[0024] Synthesis of N-(2-Methylphenyl)Butanamide (VII)

[0025] 1128.6 g of o-toluidine were initially charged in 500 ml oftoluene and heated to 90° C. 134.3 g of butyryl chloride were addeddropwise within 2 hours. After completed addition, the mixture washeated to reflux and stirring continued at this temperature until theend of gas formation. The mixture was cooled to 70° C., 12 ml ofmethanol were added and stirring was continued for an hour. To removethe methanol, the mixture was heated and 70 ml were distilled off. 300ml of toluene were then distilled off and 400 ml of cyclohexane wereadded. The mixture was cooled to 10° C. and filtration gave 199.5 g (92%yield) of the product in 98% purity after drying.

Example 2

[0026] Synthesis of N-(4-Bromo-2-Methylphenyl)Butanamide (VIII)

[0027] 30 g of N-butyryl-o-toluidine and 150 g of glacial acetic acidwere initially charged at 30° C. A solution of 33 g of bromine in 66 gof glacial acetic acid was added with stirring and then stirring wascontinued at from 25 to 30° C. for 1 hour. 300 ml of water were thenadded to the reaction mixture which, after continued stirring for ashort time, was filtered, the crystals were washed with water and driedunder reduced pressure. 42.5 g (98% yield) ofN-(4-bromo-2-methylphenyl)butanamide were obtained in 99.4% purity.Physical data: Melting point: 146 to 147° C. IR spectrum: 3275 cm⁻¹,1649 cm⁻¹ ¹H NMR spectrum at 400 MHz: δ = 0.93 (t, 3H), 1.62 (qt, 2 H),2.19 (s, 3 H), 2.31 (t, 2 H), 7.35 (m, 2 H), 7.4 (s, 1 H), 9.27 (s. 1H).

Example 3

[0028] Synthesis of Methyl (N-butyryl)-4-Amino-3-Methylbenzoate (II)Without Additional Solvent

[0029] 90 g of N-(4-bromo-2-methylphenyl)butanamide (obtained accordingto Example 2), 1.26 g of bis(triphenylphosphin)palladium(II) chlorideand 3.78 g of triphenylphosphine were initially charged in a pressureautoclave. The autoclave was closed, purged with nitrogen and anoxygen-free solution of 78 g of tributylamine in 400 ml was added. Theautoclave was evacuated, then pressurized with carbon monoxide to 10 barand heated to 130° C. The pressure was then maintained at 14 bar for 4hours. HPLC analysis (with external standard) of the reaction mixtureshowed the formation of methyl (N-butyryl)-4-amino-3-methylbenzoate in ayield of 95%.

[0030] The reaction solution was then freed of catalyst by boiling withactivated carbon and then admixed with 500 ml of water at 80° C. At thesame time, as much methanol as possible was removed by distillation. Theproduct precipitated and was isolated by filtration. 73.4 g of colorlesscrystals (88% yield) were obtained in 99.5% purity.

Example 4

[0031] Synthesis of (II) with Additional Solvents

[0032] 20 g of compound (VIII) together with 0.56 g ofbis(triphenylphosphine)palladium(II) chloride and 3.36 g oftriphenylphosphine were initially charged in an autoclave. The autoclavewas closed and purged with nitrogen. A solution of 21.7 g oftri-n-butylamine, 100 ml of methanol, 100 ml of chlorobenzene and 400 mlof toluene which had been previously degassed and was maintained underexclusion of oxygen was added. The autoclave was evacuated and heated to120° C. At this temperature, the autoclave was pressurized with carbonmonoxide to 6 bar and the batch was stirred until no more carbonmonoxide was taken up. After cooling, the reaction mixture was withdrawnfrom the autoclave, freed of catalyst and by boiling with activatedcarbon. HPLC analysis gave a conversion of 84.4% at a selectivity of93%.

Example 5

[0033] Synthesis of N-(4-Bromo-2-Methylphenyl)butanamide (VIII) viaBromine/hydrogen Peroxide Bromination

[0034] 260 g of toluene and 85.7 g of o-toluidine were initially chargedand the solution heated to 90° C. At 85-95° C., 89.5 g of butyrylchloride were added dropwise. After the end of the addition, thedropping funnel was flushed with 86 g of toluene, then the mixture washeated to reflux and stirring was continued until gas formation hadended plus one hour of supplementary reaction time. The mixture was thencooled to 70-75° C. 8 g of methanol were added and the mixture wasstirred at 75° C. for one hour. To remove methanol and toluene, themixture was heated (110-130° C.) and they were distilled off. Toward theend of the distillation, 50 g of water were added and distilled offagain, in order to remove residual toluene. The mixture was then cooledto 90° C. 850 g of acetic acid were then added and the solution cooledto 50° C. 67.1 g of bromine were then slowly added dropwise. 28.6 g ofhydrogen peroxide solution were then metered in at 50° C. Stirring wascontinued for one hour. This gave the product in a very bulky and barelystirrable form. The suspension was added to 1500 g of water and thereactor flushed once with 500 g of acetic acid. The suspension wasfiltered and washed twice with 500 g of water each time. After drying,194.3 g of compound (VIII) (95.8% yield) was obtained in a purity of99.0%.

Example 6

[0035] Synthesis of N-(4-Bromo-2-Methylphenyl)Butanamide (VIII) viaBromine Bromination, Simultaneous Metering in

[0036] a) 3087.5 g of toluene were initially charged at 20° C. 814.2 gof o-toluidine were added. At the same time, the solution was heated to90° C. At 85-95° C., 850.3 g of butyryl chloride were metered in within2 hours. After the end of the metering in, the mixture was heated toreflux and stirring was continued until no more gas was formed plus onehour of post-reaction time. The mixture was then cooled to 70-75° C. 76g of methanol were added and the mixture was stirred for an hour at 75°C. To remove the methanol and toluene, the mixture was heated (110-130°C.) and 2600 g of distillate were distilled off. Toward the end of thedistillation, 475 g of water were added and distilled off again, inorder to remove residual toluene. Altogether, 950 g of distillate werewithdrawn. The residue was then cooled to 90° C. 3000 g of acetic acidwere then added, and the reaction solution cooled to 20° C.

[0037] b) 3000 g of water, 3000 g of acetic acid and 30 g of compound(VIII) were initially charged and heated to 50° C. 1225.5 g of bromineand the acetic acid solution of compound (VII) obtained according to a)were metered in simultaneously at 50° C. within 8 hours. Stirring wascontinued for one hour. 4000 g of water were then pumped into thereaction mixture within 2 hours which was cooled to 20° C. and stirredat 20° C. for a further hour. A suspension was transferred to a filterand filtered with suction. The product was washed with 3×2375 g ofwater. After drying, 1755.6 g of compound (VIII) (90.2% yield) wereobtained in a purity of 99.0%.

Example 7

[0038] Synthesis of N-(4-Bromo-2-Methylphenyl)Butanamide (VIII) viaBromine/hydrogen Peroxide Bromination, Simultaneous Metering in

[0039] a) 823.3 g of toluene were initially charged at 20° C. 217.1 g ofo-toluidine were added. At the same time, the solution was heated to 90°C. At 85-95° C., 226.7 g of butyryl chloride were metered in within 2hours. After the end of the metering in, the mixture was heated toreflux and stirring was continued until no more gas was formed plus onehour of post-reaction time. The mixture was then cooled to 70-75° C. 20g of methanol were added and the mixture was stirred for 1 hour at 75°C. To remove the methanol and toluene, the mixture was heated (110-130°C.) and 808 g of distillate were distilled off. Toward the end of thedistillation, 126 g of water were added and distilled off again, inorder to remove residual toluene. Altogether, 934 g of distillate werewithdrawn. The residue was then cooled to 90° C. 400 g of acetic acidwere then added, and the reaction solution cooled to 20° C.

[0040] b) 933 g of water, 666 g of acetic acid and 8 g of compound(VIII) were initially charged and heated to 50° C. 161.1 g of bromineand 50% of the acetic acid solution of compound (VII) obtained accordingto a) were metered in simultaneously at 50° C. within 4 hours. 115.2 gof a 30% hydrogen peroxide solution were then metered in at the sametemperature. After the end of the reaction, 1066 g of water were addedand the mixture was cooled to 20° C. After filtration and drying, 462.7g of compound (VIII) (80% yield) were obtained in a purity of 89.6%.

1. A process for preparing methyl N-butyryl-4-amino-3-methylbenzoate,characterized in that o-toluidine is reacted with butyryl chloride togive N-butyryl-2-methylaniline, the latter is brominated to giveN-(4-bromo-2-methylphenyl)butanamide and this is converted by reactionwith carbon monoxide and methanol in the presence of a palladiumcatalyst to give methyl N-butyryl-4-amino-3-methylbenzoate.
 2. Theprocess as claimed in claim 1, characterized in that the first stage iscarried out by initially charging o-toluidine in an inert solvent andthen metering in butyryl chloride at temperatures of from 50 to 100° C.3. The process as claimed in claims 1 and 2, characterized in that thesecond stage is carried out by initially chargingN-butyryl-2-methylaniline in acetic acid, adding from 1 to 1.3 molarquantity of elemental bromine together with further acetic acid at from10 to 80° C., continuing to stir the mixture at from 10 to 80° C. forfrom 20 minutes to 3 hours, then adding a water quantity of from 0.5 to5 times the volume, removing the precipitate formed, washing it withwater and drying it under reduced pressure.
 4. The process as claimed inclaims 1 to 3, characterized in that the third step of the processaccording to the invention is carried out by initially chargingN-(4-bromo-2-methylphenyl)butanamide and a palladium catalyst into apressure vessel, then adding a mixture of methanol, optionally one ormore solvents other than methanol and a base, then pressurizing at from90 to 160° C. to 2-30 bar of carbon monoxide and maintaining thispressure until no more carbon monoxide is taken up.
 5. The process asclaimed in claims 1 to 4, characterized in that the palladium catalystsused are those of the Pd(P Ph₃)₂X₂ type where Ph=optionally substitutedphenyl and X=halogen.
 6. The process as claimed in claims 1 to 5,characterized in that a base is added in the third stage.
 7. A processfor preparing N-(4-bromo-2-methylphenyl)butanamide, characterized inthat o-toluidine is initially charged in an inert organic solvent,butyryl chloride is then metered in at temperatures of from 50 to 100°C., the solvent is removed by adding water to the melt of the amideobtained and distilling it off again, admixing the crude amide thusobtained with a solvent suitable for bromination and adding from 0.45 to0.95 of bromine per mole of the amide at temperatures of from 10 to 130°C. and, to supplement to 1 mol, an oxidant.
 8. A process for preparingN-(4-bromo-2-methylphenyl)butanamide, characterized in that butyrylchloride is metered in to o-toluidine at from 50 to 100° C., the solventis removed distillatively, and water is optionally added to the melt ofthe amide obtained and distilled off again.
 9. The process as claimed inclaim 7, characterized in that the bromination is carried out bysimultaneously metering in the bromine and the oxidant on the one handand the amide on the other hand with a tolerance of up to 20% in therespective volume flow rates.
 10. N-(⁴-Bromo-2-methylphenyl)butanamideof the formula